1. Technical Field
The invention relates to a process for the preparation 2,3 disubstituted indoles useful as pharmaceutical agents and particularly pharmaceutical agents for the treatment of hepatitis C viral (HCV) infections.
2. Background Information
Substituted indoles are useful as pharmaceutical agents. Examples of substituted indoles used as pharmaceutical agents thereof include the anti-inflammatory agents indomethacin and tropesin, the antihistamine mebhydroline, and the vasodilator vinpocetine. Other examples of indole compounds used as pharmaceutical agents are indole compounds such as disclosed in U.S. patent application Ser. No. 10/198,384 filed Jul. 7, 2002 and U.S. provisional application 60/546,213, filed Feb. 20, 2004.
One of the key aspects in the synthesis of disubstituted indoles is the coupling of the substituents at the 2,3 positions of the indole and a number of general methods have been used to perform the coupling. One method was exemplified by employing a dipyridyl zinc intermediate and a palladium catalyst as shown in U.S. provisional patent application No. 60/551,107 filed Mar. 8, 2004. This process is referred to herein as Process A.

Another approach employs the use of Pd-catalyzed indolization of 2-bromo- or chloro-anilines with internal alkynes and is described in U.S. provisional patent application No. 60/553,596, filed Mar. 16, 2004. This process is referred herein as Process B

Although Processes A and B can be used in the preparation 2,3 disubstituted indoles both processes have some limitations. When the product contains the moiety of arylbromide as in the case shown below, Process A can potentially result in the formation of polymerization product from the competing side reaction of the desired product with the nucleophile i.e. the zinc reagent.

Similarly, when the substitutents of the internal alkynes contain the moiety of vinyl bromide, vinyliodide, arylbromide and aryliodide that would compete with 2-halogen-anilines for oxidative insertion to the palladium catalyst, Process B can have poor efficiency.

Synthetic routes for preparation of arylboronic esters 1-3 via palladium-catalyzed borylation were developed by Miyaura and Murata, by reaction of bis(pinacolato)diboron 1-1 with aryl halides [Ishiyama, T.; Murata, M.; Miyaura, N. J. Org Chem. 1995, 60, 7508], or from dialkoxyhydroborane 1-2 with aryl halides or triflates [Murata, M.; Oyama, T.; Watanabe, S., Masuda, Y. J. Org Chem. 2000, 65, 164]. However, optimal reaction conditions are often varied significantly, depending upon the structures of the substrates.

Therefore, design of new process for making 2,3 disubstituted indoles is needed in the art.